Electrolytes Disturbances and Seizures

Electrolyte disturbances are frequently encountered in daily clinical practice. The diagnosis of these abnormalities is commonly made from routine laboratory findings, and they are not usually of clinical significance. However, they may sometimes lead to serious complications when overlooked or not treated appropriately. Electrolyte abnormalities may affect many organs and tissues, including the brain. Most of the clinical manifestations of these derangements are predominantly neurologic and parallel the severity of neuronal damage. Furthermore, these disorders may appear with seizures, or with rapidly progressive neurologic symptoms and signs, and thus require emergency treatment (Rose and Post, 2001; Riggs, 2002). Acute and/or severe electrolyte imbalances frequently cause seizures, and these seizures may be the sole presenting symptom. Seizures are especially common in patients with sodium disorders, hypocalcemia, and hypomagnesemia. Successful management of patient seizures begins with the establishment of an accurate diagnosis of the underlying electrolyte disturbance, because rapid identification and correction of the disturbance is necessary to control seizures and prevent permanent brain damage (Kunze, 2002; Riggs, 2002). A 61-year-old man was initially seen in the emergency department with nausea and emesis and, after several minutes, tonic–clonic seizures developed. The patient had a previous medical history of benign prostatic hyperplasia, and several hours before admission, he came to the radiology department to undergo a routine abdominal ultrasound examination. To fill his bladder before undertaking the ultrasound test, he drank a copious amount (4–5 L) of water. On physical examination, the patient was confused and disoriented. The neurologic examination was unremarkable. His serum electrolyte levels were as follows: sodium, 112 mEq/L; potassium, 3.4 mEql/L; serum osmolality, 235 mOsm/kg; and blood glucose, 124 mg/dl. Emergency computed tomography of the brain was normal. We diagnosed hyponatremic encephalopathy due to water intoxication and treated with intravenous 3% saline solution. In 48 h, the patient's serum sodium level increased to 136 mM. He made a full clinical recovery. It is clear that better training in management of electrolyte imbalances in patients with seizures is needed to reduce common and serious neurologic morbidity associated with these medical problems. We give an overview of the clinical aspects of electrolyte disturbances associated with seizures, with special regard to the pathophysiologic mechanisms involved and treatment recommendations. Electrolyte homeostasis in the central nervous system (CNS) is essential for brain function. Regulation of ionic balance is a critical process involving a complex array of molecules for moving ions into and out of the brain and involving blood–brain barrier function as well as mechanisms in the membranes of both neurons and glia. Alterations in ion gradients across cellular membranes can have direct and indirect effects on neuronal discharge and may facilitate epileptiform activities (Scwartzkroin et al., 1998). A variety of pathological states or conditions such as dehydration or renal failure are associated with substantial modifications of plasma osmolality and electrolyte balance. These conditions may overcome homeostatic brain systems and provoke profound consequences on brain metabolism and function. Clinical manifestations of electrolyte disturbances in the CNS are variable. In general, they represent functional disturbances of the brain, and, at least in the beginning, are generally not associated with morphologic changes in brain tissue. Because neurologic symptoms of electrolyte disorders are generally functional rather than structural, the neurologic manifestations of electrolyte disturbances are typically reversible (Kunze, 2002; Riggs, 2002). However, because functional dysfunction such as seizures can lead to structural alterations, it is important to treat the underlying disturbance before the pathology becomes permanent. Disorders of sodium and osmolality produce CNS neuronal depression, with encephalopathy as the major clinical manifestation; these disorders can also provoke CNS neuronal irritability. Similarly, hypercalcemia and hypermagnesemia produce CNS neuronal depression with encephalopathy. Conversely, hypocalcemia and hypomagnesemia cause mainly CNS neuronal irritability with seizures. In contrast, disorders of potassium rarely produce symptoms in the CNS but may be associated with muscle weakness as the major clinical manifestation (Victor and Ropper, 2001; Riggs, 2002) The main features of CNS neuronal depression and encephalopathy are confusion and slight cognitive disturbances. These features may be accompanied by headache, lethargy, weakness, tremor, and so on, usually without signs of focal cerebral disease or a disorder of cranial nerves (Kunze, 2002; Riggs, 2002). Electrolyte disorders frequently cause seizures (Table 1). Seizures are common in patients with sodium disorders, hypocalcemia, and hypomagnesemia (Victor and Ropper, 2001; Riggs, 2002). In such cases, seizures are usually generalized tonic–clonic, although partial seizures or other seizure types can occur. In all these cases, rapidly evolving electrolyte abnormalities are more likely to cause seizures than are those occurring gradually. For this reason, it is not possible to assign absolute levels of electrolyte above or below which seizures are likely to occur (Victor and Ropper, 2001). The correct diagnosis of seizures secondary to electrolyte abnormalities begins with a complete serum chemistry evaluation, including measurements of electrolytes, especially sodium, calcium, and magnesium. This workup should always be part of the initial diagnostic workup in adult patients with a first-time seizures (Browne and Holmes, 2001; Oguni, 2004). Such an electrolyte screen is particularly important in certain patient populations, such as the elderly, in which metabolic disturbances (e.g., hyponatremia or hypoglycemia) are common. Between 15 and 30% of acute symptomatic seizures among seniors occur in the setting of toxic–metabolic causes (LaRoche and Helmers, 2003). Further, identification and correction of electrolyte imbalances leading to seizures are needed to reduce morbidity and mortality associated with these medical problems. Thus in a review of 375 adult cases of status epilepticus (SE), 10% had a metabolic disorder as the primary etiology of their seizure; in this subset of patients, mortality was reported to be as high as 40% (DeLorenzo et al., 1992). It is important to note that laboratory screening tests, based on the American Academy of Neurology recommendations, are not routinely performed in children and should be ordered based on individual clinical circumstances (Hirtz et al., 2000). However, a thorough history and a comprehensive neurologic and general examination remain the cornerstone of the clinical diagnosis of epilepsy. Treatment of seizures secondary to electrolyte imbalances is determined by the underlying cause of the disturbance and should be guided by the clinical setting. In most cases of electrolyte imbalance, treatment with an anticonvulsant (AED) is not necessary as long as the underlying disturbance is rectified. Long-term administration of AEDs is not necessary (Victor and Ropper, 2001; Kunze, 2002; Riggs, 2002). Indeed, AEDs alone are generally ineffective if the electrolyte disorder persists. Changes in blood electrolytes may cause diffuse brain dysfunction, metabolic encephalopathy, and consequently EEG abnormalities. The EEG has been widely used to evaluate metabolic encephalopathies since 1937, when Berguer first observed slow brain activity induced by hypoglycemia (Lin, 2005). In general, the most prominent feature of the EEG record in encephalopathies (if a change occurs) is slowing of the normal background frequency. A gradual and progressive decline over the course of the disease may be noted if serial EEGs are performed. Disorganization of the record may develop gradually, and reactivity to photic or other types of external stimulation may be altered (Kaplan, 2004a). EEG evolution generally correlates well with the severity of encephalopathy. However, EEG has little specificity in differentiating etiologies in most encephalopathies. Particularly in metabolic encephalopathies, common EEG observations include a varied degree of slowing, assorted mixtures of epileptiform discharges, high incidence of triphasic waves (TWs), and (as a rule) reversibility after treatment of underlying causes (Kaplan, 2004a; Lin, 2005). The rate of change of electrolyte balance is more important in determining the degree of EEG abnormality than is the absolute level of a given electrolyte or metabolite. For instance, EEG changes are usually more severe in uremic encephalopathy if acute deterioration of renal function exists (Smith, 2005). Hyponatremia usually produces nonspecific slowing. Very low sodium levels may initially produce posterior slowing followed by diffuse delta activity correlated clinically with papilledema. However, a variety of other patterns have been described, such as TWs, burst of high-voltage rhythmic delta activity, and central high-voltage 6-Hz to 7-Hz activity with stimulation-induced paroxysms of delta waves. Although periodic lateralized epileptiform discharges may occur, full seizure activity is very rare (Reddy and Moorthy, 2001; Kaplan, 2004a). Early EEG changes associated with hypocalcemia include evolution from alpha through theta and delta dominance. Other EEG findings (generalized spikes, sharp-waves burst of delta activity with sharp components). Generalized paroxysmal discharges and absence SE have also been reported (Kapplan, 2004a). Neonatal records may show reversible 3- to 4-Hz spike–waves discharges (Kossoff, 2002). No strict correlation links serum calcium level to seizure threshold and/or EEG changes in hypocalcemia. In hypercalcemia, EEG changes (fast activity and burst of delta and theta slowing) appear when calcium levels reach ∼13 mg/dl. As calcium level increases, increased background slowing (largely frontal), paroxysmal theta/delta bursts, and TWs may appear (Juvarra et al., 1985; Kaplan, 2004a). Diffuse and more occipital spike–slow-wave complexes may be found, suggesting a calcium-mediated vasospastic effect in the posterior cerebral circulation, also noted with very high calcium levels (Kaplan, 1998). When calcium is normalized, the EEG usually improves, but only gradually. Hyponatremia is defined as a decrease in the serum sodium concentration to a level <136 mEq/L. Hyponatremia is reported to be the cause of seizures in 70% of infants younger than 6 months who lacked findings suggesting another cause (Farrar et al., 1995). The main causes of hyponatremia are listed in Table 2. The major dangers from acute hyponatremia are brain cell swelling and herniation. Serious symptoms, principally neurologic, may become evident when hyponatremia approaches 120 mM (Riggs, 2002). Brain adaptive mechanisms to changes in osmolality help explain these adverse events. When serum sodium decreases, cerebral edema is counteracted initially by an adaptive process known as the “regulatory volume decrease,” with the displacement of water from the interstitial space to the cerebrospinal fluid and then to the systemic circulation. This process is driven by hydrostatic pressure. Subsequently, the brain prevents swelling by the extrusion from brain cells of electrolytes. Partial restoration of brain volume occurs within ∼3 h (rapid adaptation), with the extrusion from brain cells of these electrolytes: sodium, potassium, and chloride. A second cellular adaptation mechanism to osmolality changes is the egress from the brain cells of organic osmolytes (osmotically active agents), primarily amino acids, which is almost fully achieved after 48 h (slow adaptation) (Gullans and Verbalis, 1993; Bhardwaj, 2006). These organic osmolytes, known previously as “idiogenic osmoles,” play an important role in this cellular adaptation to chronic osmolality changes. If the decline in serum sodium is slow and gradual (≥48 h), cerebral swelling and neurologic symptoms are minimized by these adaptive processes, even if the absolute reduction of serum sodium is large. In acute hyponatremia, a rapid decrease in serum sodium can overwhelm these protective mechanisms, causing swelling of the brain and the development of neurologic symptoms (Adrogué and Madias, 2000a; Bhardwaj, 2006). In the past, it had been assumed that the likelihood of brain damage from hyponatremia was directly related to either a rapid decline in plasma sodium or a particularly low level of plasma sodium. Recent studies have demonstrated that other factors influence outcome, including the age and the gender of the individual (with children and the most and Bhardwaj, 2006). Thus it is that have a increased with of or permanent neurologic damage as a of the hyponatremia et al., 1998). and the brain adaptive mechanisms to hyponatremia and the cerebral This is clinically because it also a and treatment of seizures. this process of adaptation by the brain is also the of the of The correction of hyponatremia a which the electrolytes rapidly in the brain but the of organic osmolytes occurs more in patients with chronic hyponatremia, it has been that rapid correction of serum a of osmolytes in of water from neurons and this process with it the of associated with and et al., and Madias, 2000a; Riggs, 2002). However, have demonstrated that not on the rate of correction of hyponatremia alone but also on brain or severe dysfunction et al., Hyponatremia has been associated with several such as and and with and et al., 2004). The of hyponatremia in of patients is even than in those et al., 2005). The to 40% with and to with on the patient et al., and 2005). factors have been reported to the of hyponatremia associated with these underlying renal and among et al., and 2005). The mechanisms and cause hyponatremia are not a of water in the to be the cause and 2004). exists on the or and hyponatremia and 2004). It is likely that a degree of individual exists for those cases in which or causes symptomatic Hyponatremia secondary to and is more common in clinical than is seen in the clinical but most of these patients are if it to develop within the first months of of plasma sodium is not for patients with or to hyponatremia (e.g., renal and may also be in patients related symptoms weakness, headache, and age is a and patients should be (Smith, 2001; et al., 2005). Treatment can of the factors as or or water and if of the or (Smith, 2001; and should be at sodium levels of mEq/L. The manifestations of hyponatremia are related to dysfunction of the CNS and are more when the decrease in serum sodium concentration is or rapid et al., and Madias, In general, symptoms of hyponatremia parallel the severity of cerebral is likely to of the patients with chronic hyponatremia are even with serum sodium concentration than et al., 1998). rarely occur the serum sodium is than 120 and are more usually associated with or are at high of symptomatic hyponatremia, as they have a of severe and rapidly evolving hyponatremia include seizures, usually generalized Seizures generally occur if the plasma sodium concentration rapidly to mEq/L; they represent an and also a medical as they are associated with high mortality (Riggs, 2002). A in the serum sodium the of reduce cerebral seizures induced by hyponatremia can be by rapid in the serum sodium concentration that only to (Adrogué and Madias, in neurologic function associated with hyponatremia may correction of the electrolyte particularly in the patient and 2003). Treatment for acute symptomatic hyponatremia be because brain may be rapid and even when clinical symptoms are (Adrogué and Madias, saline the most common treatment for acute symptomatic hyponatremia, causes a decline in brain pressure. Treatment should in serum sodium to more than 120 to mEq/L. treatment of hyponatremia with saline can be also because this can provoke of the brain that and can cause neurologic dysfunction including seizures, and even et al., and Madias, 2000a; Riggs, 2002). On the of the it to correct the sodium concentration at a rate of However, in at a for severe neurologic and a rate of to has been used and and Madias, correction appear to be well in children et al., that brain may occur in patients a correction of hyponatremia et al., et al., 2001; 2006). It is important to factors for brain such as and with and to treatment is defined as a serum sodium concentration in plasma mEq/L. hyponatremia may cause seizures, is more likely to be a of seizure activity (e.g., generalized tonic–clonic is to in muscle seizures. As is more active than osmolality of muscle increases, and water into causing The most causes of are in Table 2. The brain adaptive mechanisms that to changes in osmolality also in after of water from brain cells causes of the brain and an in brain cell to this and change in by moving electrolytes across the cell leading to partial of brain volume within a hours (rapid The of brain volume is within several (slow adaptation) as a of the of organic osmolytes et al., and Madias, Although most of the change of brain osmolality in chronic hyponatremia can be for by the changes in organic osmolytes, little of these occurs with acute development of organic electrolyte occur more than the changes in serum the degree of CNS disturbance in is related mainly to the rate at which the serum sodium In acute water is from the brain, and the acute in brain volume in in encephalopathy. In chronic CNS cells organic osmolytes, and brain is as are CNS In rapid correction of the may in cerebral as water by brain cells the of electrolytes and organic Thus the of serious neurologic due to cerebral edema et al., and Madias, Riggs, 2002). However, the major for encephalopathy and the of neuronal function in this is not well encephalopathy and can occur in the absence of changes in the CNS than brain and in brain have that the of and cellular to of the and function of brain leading to an et al., and Ropper, 2001). as in hyponatremia, the symptoms of are primarily neurologic and are related mainly to the rate at which the serum sodium et al., and Madias, is likely to neurologic symptoms than is acute sodium to levels as high as are well symptoms usually require an acute in the plasma sodium concentration to mEq/L. are associated with a high mortality particularly in (Adrogué and Madias, Brain induced by can cause of cerebral with focal and which in can provoke seizures. In are typically in cases of sodium or (Adrogué and Madias, Although rapid sodium can cause seizures, are more frequently seen rapid correction of In patients with cerebral edema may appear when the osmolality is this correction may lead to and Seizures occur in of patients treated for severe by rapid of et al., 1998). The in is to homeostasis and cell volume at a rate that The of correction on the of development of and symptoms (Adrogué and Madias, et al., 2002). The rate of correction of chronic should not this rate should prevent cerebral edema and The decrease in the serum sodium concentration in patients with in those in the disorder has over a of is of Acute may be treated more in such patients, the serum sodium concentration by is et al., et al., 2002). with may be treated with saline or The for is a if this is not should be given Because the of cerebral edema with the volume of the the volume should be to that to correct (Adrogué and Madias, saline sodium is only in of as it an of volume is defined as a plasma calcium level of or an calcium concentration mg/dl. The causes of hypocalcemia are in Table 2. The symptoms of hypocalcemia are by the degree of hypocalcemia and the of the decrease in the serum calcium concentration et al., 1998). Acute hypocalcemia primary causes increased and In the the manifestations of acute hypocalcemia are seizures and altered status (Victor and Ropper, 2001; Riggs, 2002). Generalized tonic–clonic, focal and absence or seizures can occur in hypocalcemia and may be the sole presenting (Riggs, 2002; et al., 2004). status epilepticus secondary to hypocalcemia has also been reported et al., 1998). Seizures may occur without in patients with hypocalcemia. Seizures occur in of patients with acute hypocalcemia as a medical and in of patients with symptomatic and The of treatment on the severity of symptoms and the degree of hypocalcemia. Acute hypocalcemia is an emergency that and patients with symptomatic hypocalcemia should be treated because of the associated morbidity and Treatment with intravenous calcium is the most of to of calcium should be over a of to should be at and for several with of calcium levels et al., 1998). Treatment for seizures is calcium AEDs are typically not AEDs may both and seizures may remain and et al., 2002; and 2005). the treatment of hypocalcemia should be at the underlying and calcium is commonly for is more common than hypocalcemia. However, in to hypocalcemia, seizures are rarely associated with hypercalcemia calcium level of The etiologies of hypercalcemia are in Table 2. The most common symptoms of severe hypercalcemia are those to disturbances of nervous system and function et al., Riggs, 2002). of hypercalcemia on the underlying cause of the the with which it and the physical of the A rapid to hypercalcemia frequently in neurologic dysfunction, chronic severe hypercalcemia may cause only neurologic symptoms 2000). Alterations of and rarely the main neurologic manifestations of is associated with neuronal and thus rarely causes seizures. However, encephalopathy and have been to give to seizures et al., 2005). cerebral in a patient with seizures has been by cerebral et al., 2004). The for for hypercalcemia usually the of clinical manifestations and the underlying cause of the rather than the level of serum hypercalcemia should be treated Treatment and administration of such as intravenous (e.g., or or et al., are used to decrease calcium serum mechanisms of are (e.g., of normal and and with normal saline should be at a rate of to fluid is given after has been intravenous over a or over a Treatment of the underlying disorder with is defined as a plasma concentration is for anticonvulsant treatment in and (Kaplan, 2004). The of and the increased of in the brain explain the anticonvulsant of (Kaplan, to neuronal The main causes of hypomagnesemia are in Table 2. not appear to and they may not well with serum The primary clinical findings are CNS and usually generalized tonic–clonic, can occur in and in with severe at levels (Riggs, 2002). with hypomagnesemia can be treated with (e.g., usually given in In the setting of seizures or symptomatic or severe it is to to of over a to be followed by an of to of for the If seizures the may be (Riggs, 2002; and 2003). and levels should be These should be in patients with renal other electrolyte alterations, or rarely causes symptoms in the and seizures not occur. Changes in the potassium level have and profound effects on the function of the and Thus severe potassium abnormality may provoke or muscle before CNS symptoms appear Riggs, 2002) In seizures represent an important clinical manifestation of electrolyte disturbances. Seizures are more common in patients with sodium disorders, hypocalcemia, and hypomagnesemia. Successful management of patient seizures begins with the establishment of an accurate diagnosis of the underlying electrolyte disturbances. For that reason, complete serum including measurements of electrolytes, especially sodium, calcium, and should be part of the initial diagnostic workup in adult patients with seizures. Early identification and correction of these disturbances are necessary to control seizures and prevent permanent brain as AEDs alone are generally should be of these clinical conditions and have an of the underlying medical disorders, for this may the of the disease and a rapid and